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Trinucleotide-Expansion Diseases

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Neurochemical Mechanisms in Disease

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 1))

Abstract

Many diseases, most with a strong neurodegenerative component, are now known to result from an expansion of a trinucleotide repeat sequence within the genome. In many cases, the longer the repeat the earlier the onset, and the more rapid and severe is the disease progression. Almost all of these diseases may be divided into three groups. In the first group, the expansion is either in an untranslated region/intron of the gene (e.g., fragile X syndrome, myotonic dystrophy type 1 (MD1), Friedreich ataxia, or spinocerebellar ataxia type 12 (SCA12)), or is in a DNA stretch that does not code for a protein (spinocerebellar ataxia type 8 (SCA8)). In group 1, with the exception of SCA12, the repeat triplet is not CAG. Generally, the mutations in group 1 result in low or absent levels of the protein corresponding to the affected gene and/or altered message RNA metabolism. In the second group, caused by (CAG) n expansions, the mutation is in an exon of the gene and each protein is expressed with an expanded polyglutamine (Q n ) domain. At least nine neurodegenerative diseases belong in this second group. The most common of these diseases is Huntington disease (HD). Others are dentatorubralpallidoluysian atrophy (DPLA; Haw River syndrome), spinobulbar muscular atrophy (SBMA; Kennedy disease) and seven forms of spinocerebellar ataxia [SCA1, SCA2, SCA3 (Machado–Joseph disease), SCA6, SCA7, and SCA17]. The mutated genes appear to be unrelated except for the fact that each possesses a (CAG) n /Q n expansion. These diseases are characterized by insoluble protein aggregates in the affected areas. The aggregates contain the mutated protein. The CAG-expansions are widely thought to confer a pathological gain of function to the mutated protein, although in some cases a pathological decrease of function may also contribute. In eight of the Q n -expansion disorders, the disease phenotype occurs when n is greater than about 36. Disease expansions may result in n values up to about 80, but larger values may sometimes occur. In the third group, the nucleotide expansion is in a coding exon and gives rise to an elongation of a polyalanine (A n ) stretch in the mutated expressed protein. At least nine diseases have been shown to be due to an A n expansion. Eight of the mutations are in transcription factors, and in one case the mutation is in the polyadenylate-binding protein. The disease phenotypes variably include mental retardation and malformations of the brain, genitourinary tract, skull, and digits. Both the normal size of the amino acid repeat and the pathological length of the repeat tend to be smaller in the A n -expansion diseases than in the Q n -expansion diseases. Although many of the trinucleotide-expansion diseases are rare (some exceedingly rare), they offer insights into pathophysiological processes that may pertain to the more common neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease (PD).

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Abbreviations

AD:

Alzheimer disease

ARX:

Aristaless-related homeobox

BDNF:

Brain-derived neurotrophic factor

BPES:

Blepharophimosis, ptosis and epicanthus inversus

CBP:

CREB binding protein

CCD:

Cleidocranial dysplasia

CCHS:

Congenital central hypoventilation syndrome

CREB:

cAMP response-element-binding

DM:

Myotonic dystrophy

DM1:

Myotonic dystrophy type 1

DM2:

Myotonic dystrophy type 2

DMPK:

Dystrophia myotonica protein kinase

DRPLA:

Dentatorubral-pallidoluysian atrophy

FMRP:

Fragile mental retardation protein 1

FRAXE:

Fragile XE syndrome

FRDA:

Friedreich ataxia

TXTAS:

Fragile X tremor/ataxia syndrome

GST:

Glutathione S-transferase

HD:

Huntington disease

HFGS:

Hand–foot–genital syndrome

HPE:

Holoprosencephaly

Htt:

Huntingtin

ISSX:

X-linked infantile spasm syndrome

MBNL:

Muscleblind-like

MRX:

Sex-linked mental retardation

NMDAR:

N-methyl-D-aspartate receptor

NRSE:

Neuronal restrictive silencer element

OPMD:

Oculopharyngeal muscular dystrophy

PD:

Parkinson disease

PRTS:

Partington syndrome

PT:

Permeability transition

SBMA:

Spinobulbar muscular atrophy

SCA:

Spinocerebellar ataxia

SPD:

Synpolydactyly type II

TBP:

TATA-binding protein

TG:

Transglutaminase

UTR:

5′-Untranslated region

WS:

West syndrome

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Acknowledgments

We thank Dr. John T. Pinto for helpful suggestions. Part of the work cited from the authors’ laboratory was supported by NIH grant 2P01 AG14930.

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  1. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA

    Arthur J. L. Cooper

  2. Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

    John P. Blass

  3. Departments of Neurology, Neurosciences, and Medicine, Weill Medical College of Cornell University, New York, NY, 10021, USA

    John P. Blass

  4. Burke Medical Research Institute, White Plains, NY, 10605, USA

    John P. Blass

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Correspondence to Arthur J. L. Cooper .

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    John P. Blass

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Cooper, A.J.L., Blass, J.P. (2011). Trinucleotide-Expansion Diseases. In: Blass, J. (eds) Neurochemical Mechanisms in Disease. Advances in Neurobiology, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7104-3_11

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